New diagnostic methods for early detection of inborn errors of metabolism in Estonia
Kuupäev
2018-11-16
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
Pärilikud ainevahetushaigused (AVH-d) on organismi biokeemilise tasakaalu häired, mida põhjustavad monogeensed geenimutatsioonid. Kuigi tegemist on kaasasündinud haigustega, puuduvad enamikul lastest sünnihetkel sümptomid, mis ilmnevad hiljem ja on sageli pöördumatud ning eluiga lühendavad. Sestap muutub järjest olulisemaks pärilike AVH varajane diagnostika, tagamaks asjakohane pere nõustamine, sünnieelne diagnostika ning võimalusel ka ravi. Sellest ajendatuna on vastsündinute sõeltestimise programmid pidevas muutumises, et tuvastada efektiivsemalt ravitavaid AVH-i asümptoomses perioodis. Kuid kahjuks pole kõik kaasasündinud AVH-d nagu mitokondriaalsed haigused (MH) sõeltestitavad ning molekulaarselt kinnitatud diagnoosini jõudmine on vahel väga keeruline, kuna kliinilised probleemid ja nende algusaeg on äärmiselt varieeruvad ka sama pere liikmete seas. Samas on üksikutes teadustöödes hakatud valitud patsientidel diagnoosi leidmiseks rakendama kogu eksoomi sekveneerimist, mis kliinilises töös on veel minimaalselt kasutust leidnud.
Käesolevas uuringus töötati välja Eesti jaoks sobivaim vastsündinute laiendatud sõeltestimise meetod ja ülesehitus, mida rakendati 54 899 vastsündinul ning 29-l tuvastati pärilik AVH, seega on uuritavate haiguste esinemissagedus Eestis 1:1893. Enim diagnoositi kaasasündinud omandatud vitamiin B12 puudulikkust, mille esinemissagedus on 1:2959. Teisest doktoritöö osast järeldub, et kliinilises töös on kogu eksoomi sekveneerimine lapseeas alanud MH kahtlusega patsientidel efektiivne: 28-st 17-l tuvastati haigusseoselised geenimutatsioonid, seega on saagis väga kõrge – 61%. Ka töötati välja ning võeti kasutusele mtDNA analüüsimeetod standardsel kogu eksoomi sekveneerimisel. Töö teist osa ilmestavad kolm haigusjuhtu. Neist esimeses kirjeldati esmakordselt patsiente, kellel esinevad liitheterosügootsena mutatsioonid CACNA1A geenis. Teises kirjeldati esmakordselt uustekkest mutatsioon SLC25A4 geenis, mis põhjustab kolmanda, eelnevatest selgelt eristuva, kliinilise fenotüübi. Kolmandas presenteeriti patsiente uustekkese mutatsiooniga NDUFB11 geenis, mis põhjustab varieeruvat kliinilist fenotüüpi, kuid prevaleeruvad sümptomid on histiotsütoidne kardiomüopaatia ja kaasasündinud sideroblastne aneemia.
Inborn errors of metabolism are monogenic disorders causing a biochemical imbalance in the organism. Although these disorders are congenital, the newborns are often symptom-free and signs of the disorder occur later, are often irreversible, and reduce lifespan. Therefore, an early diagnosis is imperative in order to provide appropriate family counseling, prenatal diagnosis and treatment. This has led to the continuous improvement of neonatal screening programs to identify disorders in the asymptomatic period. Unfortunately, newborn screening cannot identify all congenital metabolic disorders, such as mitochondrial disorders (MD). The molecularly confirmed diagnosis is often very difficult to achieve, as clinical problems and their onset are extremely variable, even among members of the family. Therefore, few research groups have implemented the whole exome sequencing (WES) in selected patients to reach the diagnosis, but this method has barely used in clinical practice. The current study clarifies the most suitable methodology and structure of the expanded newborn screening program for Estonia, which was applied to 54 899 newborns and 29 of them were identified with the congenital metabolic disorder. Therefore, the prevalence of the tested diseases is 1:1893 in Estonia. The most frequent diagnosis was congenital acquired vitamin B12 deficiency with prevalence of 1:2959. The second part of the dissertation evaluates the effectiveness of WES analysis in clinical practice in patients with suspicion of childhood-onset MD. Disease-causing gene variants were found in 17 out of 28 patients (61%). Furthermore, the analysis of mtDNA from standard WES reads was also worked out and implemented in clinical work. The second part of the work also includes three well-described patients, together with the investigations that have led to the first-ever description of compound heterozygous mutations in the CACNA1A gene; the discovery of a novel de novo mutation in the SLC25A4 gene, which causes the third distinct clinical phenotype associated with this gene; and the presentation of the novel mutation in the NDUFB11 gene along with the expansion of the variable clinical phenotype, although the predominant symptoms are histiocytoid cardiomyopathy and congenital sideroblastic anemia.
Inborn errors of metabolism are monogenic disorders causing a biochemical imbalance in the organism. Although these disorders are congenital, the newborns are often symptom-free and signs of the disorder occur later, are often irreversible, and reduce lifespan. Therefore, an early diagnosis is imperative in order to provide appropriate family counseling, prenatal diagnosis and treatment. This has led to the continuous improvement of neonatal screening programs to identify disorders in the asymptomatic period. Unfortunately, newborn screening cannot identify all congenital metabolic disorders, such as mitochondrial disorders (MD). The molecularly confirmed diagnosis is often very difficult to achieve, as clinical problems and their onset are extremely variable, even among members of the family. Therefore, few research groups have implemented the whole exome sequencing (WES) in selected patients to reach the diagnosis, but this method has barely used in clinical practice. The current study clarifies the most suitable methodology and structure of the expanded newborn screening program for Estonia, which was applied to 54 899 newborns and 29 of them were identified with the congenital metabolic disorder. Therefore, the prevalence of the tested diseases is 1:1893 in Estonia. The most frequent diagnosis was congenital acquired vitamin B12 deficiency with prevalence of 1:2959. The second part of the dissertation evaluates the effectiveness of WES analysis in clinical practice in patients with suspicion of childhood-onset MD. Disease-causing gene variants were found in 17 out of 28 patients (61%). Furthermore, the analysis of mtDNA from standard WES reads was also worked out and implemented in clinical work. The second part of the work also includes three well-described patients, together with the investigations that have led to the first-ever description of compound heterozygous mutations in the CACNA1A gene; the discovery of a novel de novo mutation in the SLC25A4 gene, which causes the third distinct clinical phenotype associated with this gene; and the presentation of the novel mutation in the NDUFB11 gene along with the expansion of the variable clinical phenotype, although the predominant symptoms are histiocytoid cardiomyopathy and congenital sideroblastic anemia.
Kirjeldus
Väitekirja elektrooniline versioon ei sisalda publikatsioone
Märksõnad
congenital diseases, newborns, skriining, metabolic diseases, mitochondrial diseases, Estonia